HYPERINSULINEMIA INCREASES PLASMA ACTIVITY OF PAI-1 IN-VIVO INDEPENDENTLY OF ACUTE-PHASE REACTION

Background and objective: Hyperinsulinemia attributable to augmented c oncentrations of insulin and proinsulin in plasma increases plasma PAI -1 activity in vivo and may contribute to acceleration of atherogenesi s in patients with non-insulin-dependent diabetes mellitus (NIDDM). Th e present study is designed to verify that the increase in PAI-1 activ ity is specifically attributable to insulin and proinsulin and not to an acute phase reaction possibly triggered by endotoxins. Methods and results: To simulate hyper(pro)insulinemia seen with NIDDM, equimolar concentrations of insulin (1 IU/kg, n = 17), proinsulin (n = 16), C-pe ptide (n = 4), and placebo (n = 16) were infused intravenously over 1 h in 53 conscious rabbits maintained euglycemic. At 3 h plasma PAI-1 a ctivity was significantly higher with insulin (15.8 +/- 1.4 AU/ml, +/- SEM) and proinsulin (17.2 +/- 1.5 AU/ml) than with C-peptide (7.4 +/- 0.6 AU/ml) and placebo (6.2 +/- 0.6 AU/ml, p < 0.001). In all reagents and vehicles used no endotoxin could be detected. Both acute phase re actants tested, fibrinogen at 24 h and t-PA activity at 1 h, did not d iffer between the four treatment groups. Conclusions: With the exclusi on of endotoxin contamination and the comparable time courses of plasm a fibrinogen concentration and t-PA activity among all treatment group s, induction of PAI-1 activity in plasma can be attributed to specific action by insulin and proinsulin rather than manifestation of an acut e phase reaction.